Bone remodeling is an important process that must be precisely controlled in order to maintain a healthy life, but the signaling pathways that contro this process are incompletely understood. This exploratory project takes advantage of exciting new findings on a novel signaling pathway (i.e., the Kindlin-2 pathway) and seeks to define its role in bone remodeling. Studies by the applicants have shown that loss of Kindlin-2 in osteoblasts (OBs) or that of Migfilin, a Kindlin-2 binding partner, results in severe osteopenia in mice, suggesting a critical role of Kindlin-2 and Migfilin in bone remodeling. Depletion of either Kindlin-2 or Migfilin impairs OB functions and increased the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in OBs, a major osteoclastogenic factor. Furthermore, there is evidence suggesting that Kindlin-2 localizes to the nuclei and regulates OB gene expression and differentiation. Based on these and other studies, the applicants hypothesize that Kindlin-2 expression in OBs plays a critical role in controlling bone remodeling and it functions in this process through interaction with Migfilin and nuclear translocation. To test this the applicants propose studies with the following two aims. Aim 1 is to determine the role of Kindlin-2 in OBs in vivo. The applicants will analyze in detail the effects of Kindlin-2 deficiency on OB behavior and bone formation in vivo using OB-specific Kindlin-2 knockout mice. Furthermore, the applicants will determine the role of Kindlin-2 in regulation of RANKL expression in OBs, OCL differentiation and bone resorption in vivo. Aim 2 is to define the molecular and cellular mechanisms by which Kindlin-2 functions in OBs. The applicants will determine the roles of Kindlin-2 interaction with Migfilin and nuclear translocation in regulation f OB functions. Furthermore, the applicants will assess whether Kindlin-2 and Migfilin interact genetically in regulation of bone remodeling. Although this project is of relatively high risk due o the novelty of the proposed signaling pathway and mechanism in bone remodeling, it is highly rewarding, as if our hypothesis is validated by the proposed studies, this will open a new avenue of research on the mechanisms that control bone remodeling and new strategies for treatment of bone diseases.